The discovery of [1-(4-dimethylamino-benzyl)-piperidin-4-yl]-[4-(3,3-dimethylbutyl)-phen yl]-(3-methyl-but-2-enyl)-amine, an N-type Ca+2 channel blocker with oral activity for analgesia

Bioorg Med Chem. 2000 Jun;8(6):1203-12. doi: 10.1016/s0968-0896(00)00077-8.

Abstract

Our drug discovery efforts for N-type calcium channel blockers in the 4-piperidinylaniline series led to the discovery of an orally active analgesic agent 26.1-[4-Dimethylamino-benzyl)-piperidin-4-yl]-[4-(3,3-dimethyl-but yl)-phenyl]-(3-methyl-but-2-enyl)amine (26) showed high affinity to functionally block N-type calcium channels (IC50=0.7 microM in the IMR32 assay) and exhibited high efficacy in the anti-writhing analgesia test with mice (ED50=12 mg/kg by po and 4 mg/kg by iv). In this report, the rationale for the design, synthesis, biological evaluation, and pharmacokinetics of this series of blockers is described.

MeSH terms

  • Administration, Oral
  • Analgesics / chemical synthesis
  • Analgesics / chemistry*
  • Analgesics / pharmacology*
  • Aniline Compounds / chemical synthesis
  • Aniline Compounds / chemistry*
  • Aniline Compounds / pharmacology*
  • Animals
  • Calcium Channel Blockers / administration & dosage
  • Calcium Channel Blockers / chemical synthesis
  • Calcium Channel Blockers / chemistry*
  • Calcium Channel Blockers / pharmacology*
  • Calcium Channels, N-Type / drug effects*
  • Cell Line
  • Magnetic Resonance Spectroscopy
  • Male
  • Mass Spectrometry
  • Mice
  • Molecular Structure
  • Piperidines / chemical synthesis
  • Piperidines / chemistry*
  • Piperidines / pharmacology*
  • Rats
  • Rats, Wistar

Substances

  • (1-(4-dimethylaminobenzyl)piperidin-4-yl)-4((3,3-dimethylbutyl)phenyl)-(3-methylbut-2-enyl)amine
  • Analgesics
  • Aniline Compounds
  • Calcium Channel Blockers
  • Calcium Channels, N-Type
  • Piperidines